A randomized trial of exercise on well-being and function following breast cancer surgery: the RESTORE trial

Objectives  

This study aimed to determine the effect of a moderate, tailored exercise program on health-related quality of life, physical function, and arm volume in women receiving treatment for nonmetastatic breast cancer.     

Vindesine-mitoxantrone (VM) versus vindesine-4'-epidoxorubicin (VE) in metastatic breast cancer: a prospective randomized trial

182 patients with metastatic breast cancer were randomized to V (mg/m2 i.v.) and M (10 mg/m2 i.v.) or E (40 mg/m2 i.v.) every 3 weeks x 3 and then every 4 weeks; they were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by prior chemotherapy. In a preliminary analysis there is a significant difference regarding frequency of alopecia (WHO Grade 3 or 4) favoring regimen VM; gastrointestinal, hematologic and neurotoxic side effects were mild and similar for both groups. Of 114 evaluable women there is a response rate (CR + PR) of 26% and 34% for VM and VE respectively (n.s.), and there is no significant difference between the 2 groups in time to progression and survival. Both regimens are well tolerated and seem to be equally effective. The median follow-up time is too short to draw final conclusions.     

A prospective randomized trial of doxorubicin versus idarubicin in the treatment of advanced breast cancer

Seventy-six patients with advanced breast cancer were entered into the current study. They were randomized to receive either idarubicin (IDA) 45 mg/m2 orally or doxorubicin (DX) 75 mg/m2 intravenously (IV), both drugs being administered every 3 weeks. Among 37 evaluable patients who received DX treatment the overall response rate was 46%, whereas it was 21% in 34 evaluable patients treated with IDA. This difference was statistically significant. In previously untreated patients the response rate with DX was 60% compared to 29% with IDA. Patients with prior chemotherapy had 29% response rate to DX in contrast to 12% with IDA. The median time to response, the median response duration, and the median time to progression were similar in both groups. The median survival of all patients was 20 months in DX arm and 14 months in IDA arm (95% confidence limits 16.69-23.31 and 10.77-17.23, respectively; P = 0.09). Both treatments produced equivalent incidence and severity of myelotoxicity. Gastrointestinal toxicity and alopecia were significantly lower in patients receiving IDA. As for cardiotoxicity, four cases of congestive heart failure were recorded among patients treated with DX whereas no cases occurred in the IDA group. The results of this study indicate that, although DX remains the best single agent available in the treatment of breast cancer, IDA may have a role in selected patients with this disease.     

Targeting low molecular weight cyclin E (LMW-E) in breast cancer

Low molecular weight cyclin E (LMW-E) plays an important oncogenic role in breast cancer. LMW-E, which is not found in normal tissue, can promote the formation of aggressive tumors and can lead to increased genomic instability and tumorigenesis. Additionally, breast cancer patients whose tumors express LMW-E have a very poor prognosis. Therefore, we investigated LMW-E as a potential specific target for treatment either alone or in combination therapy. We hypothesized that because LMW-E binds to CDK2 more efficiently than full length cyclin E, resulting in increased activity, CDK inhibitors could be used to target tumors with LMW-E bound to CDK2. To test the hypothesis, an inducible full length and LMW-E MCF7-Tet-On system was established. Cyclin E (full length (EL) or LMW-E) is only expressed upon induction of the transgene. The doubling times of cells were unchanged when the transgenes were induced. However, upon induction, the kinase activity associated with LMW-E was much higher than that in the EL induced cells or any of the uninduced cells. Additionally only the LMW-E induced cells underwent chromosome aberrations and increased polyploidy. By examining changes in proliferation and survival in cells with induced full length and LMW-E, CDK inhibitors alone were determined to be insufficient to specifically inhibit LMW-E expressing cells. However, in combination with Doxorubicin, the CDK inhibitor, Roscovitine (Seliciclib, CYC202), synergistically led to increased cell death in LMW-E expressing cells. Clinically, the combination of CDK inhibitors and chemotherapy such as Doxorubicin provides a viable personalized treatment strategy for those breast cancer patients whose tumors express the LMW-E.     

Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized,double-blind,placebo-controlled trial

Depression, anxiety and sleep disturbances are known problems in patients with breast cancer. The effect of melatonin as an antidepressant in humans with cancer has not been investigated. We investigated whether melatonin could lower the risk of depressive symptoms in women with breast cancer in a three-month period after surgery and assessed the effect of melatonin on subjective parameters: anxiety, sleep, general well-being, fatigue, pain and sleepiness. Randomized, double-blind, placebo-controlled trial undertaken from July 2011 to December 2012 at a department of breast surgery in Copenhagen, Denmark. Women, 30–75 years, undergoing surgery for breast cancer and without signs of depression on Major Depression Inventory (MDI) were included 1 week before surgery and received 6 mg oral melatonin or placebo for 3 months. The primary outcome was the incidence of depressive symptoms measured by MDI. The secondary outcomes were area under the curve (AUC) for the subjective parameters. 54 patients were randomized to melatonin (n = 28) or placebo (n = 26) and 11 withdrew from the study (10 placebo group and 1 melatonin group, P = 0.002). The risk of developing depressive symptoms was significantly lower with melatonin than with placebo (3 [11 %] of 27 vs. 9 [45 %] of 20; relative risk 0.25 [95 % CI 0.077–0.80]), giving a NNT of 3.0 [95 % CI 1.7–11.0]. No significant differences were found between AUC for the subjective parameters. No differences in side effects were found (P = 0.78). Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery.     

A prospective, randomized trial of pre-operative and intraoperative radiotherapy versus surgery alone in resectable gastric cancer

INTRODUCTION: Worldwide, gastric cancer remains one of the most common malignancies. Discouraging survival rates after surgical treatment promote the study of adjuvant therapy. A prospectively, randomized, controlled clinical trial was performed in order to determine whether pre-operative and intraoperative radiotherapy improves treatment results of gastrectomy for stomach carcinoma. METHODS: From 1993 to 1998, 112 patients were randomized and underwent exploratory laparotomy; among them 78 satisfied protocol requirements and entered in the trial. Patients in the experimental group were treated with pre-operative radiotherapy (20 Gy/5 days), gastrectomy and intraoperative radiotherapy (20 Gy using 8-12 electrons). Patients in the control group underwent surgery alone. RESULTS: Incidence and distribution of post-operative complications were similar in both groups except significantly higher incidence of pancreatitis after surgical treatment. No late radiation-related morbidity was registered. There was no significant difference in survival between the two treatment groups (Chi(2)=1.026, df=1, P=0. 311) as well as in N0 (Chi(2)=0.0029, df=1, P=0.956) and T1-2 subgroups (Chi(2)=0.1928, df=1, P=0.660). In contrast, combined treatment had marked survival advantage in more advanced stages: in the case of lymph-node involvement (Chi(2)=4.19, df=1, P=0.04) and extragastric tumour extension (Chi(2)=4.118, df=1, P=0.042). CONCLUSION: The proposed intensive treatment programme is feasible, shows good acute and late tolerance and has the potential to improve survival in patients with locally advanced gastric cancer.     

Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: a randomized prospective trial

BACKGROUND: This study was designed to replicate our earlier finding that intensive group therapy extended survival time of women with metastatic breast cancer. Subsequent findings concerning the question of whether such psychosocial support affects survival have been mixed. METHODS: One hundred twenty-five women with confirmed metastatic (n = 122) or locally recurrent (n = 3) breast cancer were randomly assigned either to the supportive-expressive group therapy condition (n = 64), where they received educational materials plus weekly supportive-expressive group therapy, or to the control condition (n = 61), where they received only educational materials for a minimum of 1 year. The treatment, 90 minutes once a week, was designed to build new bonds of social support, encourage expression of emotion, deal with fears of dying and death, help restructure life priorities, improve communication with family members and healthcare professionals, and enhance control of pain and anxiety. RESULTS: Overall mortality after 14 years was 86%; median survival time was 32.8 months. No overall statistically significant effect of treatment on survival was found for treatment (median, 30.7 months) compared with control (median, 33.3 months) patients, but there was a statistically significant intervention site-by-condition interaction. Exploratory moderator analysis to explain that interaction revealed a significant overall interaction between estrogen-receptor (ER) status and treatment condition (P = .002) such that among the 25 ER-negative participants, those randomized to treatment survived longer (median, 29.8 months) than ER-negative controls (median, 9.3 months), whereas the ER-positive participants showed no treatment effect. CONCLUSIONS: The earlier finding that longer survival was associated with supportive-expressive group therapy was not replicated. Although it is possible that psychosocial effects on survival are relevant to a small subsample of women who are more refractory to current hormonal treatments, further research is required to investigate subgroup differences.     

High dose versus low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer

One hundred and twenty-four patients with advanced breast cancer were randomly allocated to treatment with either low dose (300 mg/day) or high dose (1000 mg/day) oral medroxyprogesterone acetate. The objective response rate was 24% for both treatment groups. For premenopausal patients, responses were achieved in two out of four on low dose and three out of six on high dose therapy (overall 5 out of 10 responders). No significant differences in response were seen in relation to previous endocrine therapy or site of disease. Both treatments were associated with a high incidence of bone pain relief (43 and 52%) but a low objective response rate (13%) in bone. Median response duration (10 vs. 11 months) and survival (13 vs. 11 months) were not significantly different for the two treatments. Both treatments were in general well tolerated, but toxicity was greater with the high dose treatment. Low dose oral medroxyprogesterone acetate is as effective as high dose therapy in the treatment of advanced breast cancer, and is cheaper and less toxic.     

低分子肝素对卵巢肿瘤化疗诱导凝血功能活化的影响

目的:研究化疗前应用单一剂量低分子肝素对卵巢癌凝血功能的影响。方法:选择30例卵巢癌患者为单纯化疗组,20例卵巢癌患者为化疗+低分子肝素组,分别检测化疗前和化疗后1、24和48 h血浆纤维蛋白原以及D-二聚体的含量。结果:单纯化疗组化疗后血浆纤维蛋白原含量均低于化疗前,其中化疗后24 h与化疗前相比,差异有统计学意义,P<0.01;D-二聚体水平化疗后显著高于化疗前,其中化疗后24和48 h与化疗前相比,差异均有统计学意义,P<0.01。化疗+低分子肝素组化疗后血浆纤维蛋白原含量也低于化疗前,其中化疗后24和48 h与化疗前相比,差异均有统计学意义,P<0.01;D-二聚体水平化疗后与化疗前相比升高不明显,差异无统计学意义,P>0.05。结论:化疗能显著促进卵巢癌患者凝血和纤溶水平的升高。化疗前应用单一剂量的低分子肝素能抑制凝血功能的活化。     

Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparin versus urokinase versus control. Results of a prospective randomized clinical trial (colorectal adenocarcinoma trial I)

This prospectively randomized clinical trial was carried out in four Dutch hospitals to reduce the development of metachronous liver metastases and to get a better survival in patients with colorectal malignancies after surgically radical en bloc resection of the primary tumor and the regional lymph nodes. Three hundred seventeen patients were randomized to participate in three trial arms. One group of patients was treated by surgery alone (control group); in the other patients a catheter was placed in the dilated umbilical vein and advanced until the tip was lying in the left branch of the portal vein. Fifty percent of these patients got immediate postoperative portal infusion with 1 g 5-fluorouracil (5-FU) and 5000 U heparin daily for 7 days; the others received portal vein infusion with urokinase 10.000 U/hour for 24 hours only. Three hundred four patients were eligible. Overall hospital mortality was 3.6% (11 patients) and was not influenced by adjuvant treatment. After a median follow-up of 44 months 66 patients have died with relapse and 21 as a result of other causes. The chance of developing liver metastases and other distant metastases after portal infusion with 5-FU/heparin was one third of the chance in the control group (P less than 0.001). Only an insignificant reduction of the average death rate in the 5-FU/heparin group was found. In the urokinase group no significant effect in reducing metastases or in survival was noted. Before recommending cytotoxic portal infusion as an adjuvant treatment in patients with colorectal cancer, detailed analysis of other ongoing portal infusion studies has to be awaited and careful calculations have to be made regarding how many patients really can be saved by this treatment.     

Misonidazole and radiotherapy in lung cancer: A randomized double-blind trial

Forty-six patients with inoperable bronchial cancer have been treated by a fractionated course of radiotherapy with misonidazole or placebo. The main purpose of the administration of the drug to these patients was to determine tumor response and safe dosage in clinical radiotherapy. It seems possible to enhance the radiosensitivity of human squamous cell cancer by misonidazole.     

The effect of low molecular weight heparin on survival in patients with advanced malignancy.

PURPOSE: Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS: Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS: In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.     

Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism.

PURPOSE: Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism. PATIENTS AND METHODS: Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups. RESULTS: During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02). CONCLUSION: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.     

A double-blind,placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial

BackgroundMultiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome.Patients and methodsIn this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month.ResultsWithin this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70).ConclusionCreatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.     

A prospective randomized trial comparing epirubicin and doxorubicin in advanced or recurrent breast cancer

A randomized clinical trial comparing epirubicin (EPI) and doxorubicin (DX) was conducted in patients with advanced or recurrent breast cancer. The dosage employed was 60 mg/m2 for EPI and 40 mg/m2 for DX at intervals of three weeks. There were 40 patients entered into the EPI group and 39 into the DX group. Background factors analysed were well balanced in both groups. The response rate was 56.3% in the EPI group (5 CR and 13 PR among 32 evaluable patients), and 35.5% in the DX group (1 CR and 10 PR among 31 evaluable patients), and the difference between both groups was statistically significant (P less than 0.05) by U-test. The response duration and time to response showed no significant difference between both groups. The incidences and grades of hematologic and non-hematologic toxicities were nearly identical. We conclude that EPI is a useful drug for the treatment of advanced breast cancer.     

低分子肝素联合化疗治疗非小细胞肺癌的随机研究

目的:观察低分子肝素联合MVP方案治疗晚期非小细胞肺癌的短期疗效,毒副反应及对生存期的影响。方法:46例非小细胞肺癌随机分为两组,A组(治疗组)为MVP+肝素;B组(对照组)为单纯MVP。两组均接受MVP方案两周期。化疗方案:MMC 6 mg/m2,VDS 3 mg/m2×2,DDP 90 mg/m2。治疗组加用低分子肝素5 000u皮下注射,化疗前三天起,每日二次,共7天。结果:治疗组有效率56.5％(13/23),中位生存期12.1月(95％CI:8.52～14.64月),一年生存率52.2％。对照组有效率39.1％(9/23),中位生存期8.4月(95％CI:6.15-10.85月),一年生存率34.8％。治疗组中位生存期及一年生存率明显大于对照组(P<0.05)。主要毒副反应为Ⅱ-Ⅲ度血液毒性,消化道反应均为Ⅰ-Ⅱ度。两组间毒副反应比较无显著差异(P>0.05)。结论:低分子肝素联合MVP方案能提高NSCLC的化疗疗效,延长生存,不增加毒副反应。     

A prospective randomized trial of HLA-matched versus mismatched single-donor platelet transfusions in cancer patients

The use of histocompatability antigen (HLA)-matched platelets has been advocated for the support of thrombocytopenic cancer patients. We randomized 78 newly diagnosed cancer patients prospectively (before thrombocytopenia) to receive either HLA-matched or mismatched single-donor platelet transfusions. Three hundred forty-one platelet transfusions were given for 80 separate episodes of therapy-induced thrombocytopenia in 33 patients. Forty-five patients receiving intensive chemotherapy did not develop significant (less than 20,000 platelets/mm3) thrombocytopenia and did not receive a platelet transfusion. No marked difference was observed between the matched and mismatched groups in regard to number of total platelet transfusions per patient (median, 3 vs. 5, respectively; P = 0.076), number of platelet transfusions per episode (median, 3.0 vs. 3.5, respectively; P = 0.28), or days between transfusions (median, 2 vs. 2, respectively, P greater than 0.4). Bleeding episodes, although rare, tended to be of increased severity in the mismatched group. Febrile patients receiving mismatched platelets tended to have a lower posttransfusion increment increase than their nonfebrile counterparts (P = 0.068), although a similar trend could not be demonstrated between febrile and nonfebrile patients who received matched platelets (P = 0.22). Patients treated as outpatients had significantly higher posttransfusion increments than when transfused as inpatients when they were given mismatched platelets (P less than 0.0005). Development of antiplatelet antibody did not appear to affect response to platelet transfusions. Only one patient developed sustained high-level antibody titers. In patients where thrombocytopenia was significant, the transfusion of HLA-matched platelets did not appear to offer a significant advantage. However, HLA-matched platelet transfusions tended to be associated with higher posttransfusion increments in febrile patients and a trend toward fewer severe bleeding episodes. A multi-institution trial containing a large number of patients is needed to evaluate trends observed in this study.     

Prulifloxacin versus levofloxacin in the treatment of chronic bacterial prostatitis: a prospective, randomized, double-blind trial

Ninety-six patients with chronic bacterial prostatitis (CBP) and evidence of infection were randomized to receive a 4-week oral course of either prulifloxacin (a new fluoroquinolone) 600 mg or levofloxacin 500 mg once daily. They were evaluated with the Meares-Stamey test and the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) at baseline and one week after therapy completion. Patients with microbiological eradication were evaluated again with the Meares-Stamey test 6 months after therapy completion. The microbiological eradication rate was 72.73% for prulifloxacin and 71.11% for levofloxacin (p=0.86) and the reduction in the NIH-CPSI was 10.75 and 10.73, respectively (p=0.98). Safety was comparable, with 18.18% adverse events for prulifloxacin and 22.22% for levofloxacin (p=0.79). Thus, a 4-week course of prulifloxacin 600 mg once daily is at least as effective and safe as levofloxacin 500 mg once daily in the treatment of CBP.